Skin, among other things, is composed of epidermal and dermal layers. The dermal layer provides the support and blood supply for the epidermis. The dermal layer is also important in maintaining the elasticity and appearance of the skin. The dermis is largely comprised of cells and extracellular matrix (“ECM”). The composition of the ECM is largely determined by fibroblasts that elaborate various components such as collagens, elastins, and proteoglycans. With increasing age, as well as exposure to the sun and environmental contaminants, there is progressive thinning and disruption of the supporting dermis. This leads directly to sagging and consequent furrowing of the epidermis, i.e., the formation of wrinkles. (See, for example, Oikarinen A. The aging of skin: chronoaging versus photoaging. Photodermatol Photoimmunol Photomed 7: 3-4, 1990).
It is well established in the art that fetal skin is fundamentally different from adult skin. For instance, after injury, adult skin repairs through scar formation, a process characterized by the replacement of injured tissues with a disorganized deposition of collagen and various ECM components, referred to collectively as a “scar.” In contrast, fetal skin repair occurs by cellular regeneration and restoration of normal skin architecture through organized deposition of collagen and ECM components to effect scarless repair. Studies have shown that the capabilities for scarless skin repair is one quality of fetal skin, and does not require the fetal immune system, fetal serum, or amniotic fluid (Bleacher J C, et al., J Pediatr Surg 28: 1312-4, 1993); Ihara S, Motobayashi Y., Development 114: 573-82. 1992). For example, isolated human fetal skin transplanted into athymic mice heals without producing typical scar tissue (Adzick N S, Lorenz H P., Ann Surg 220: 10-8. 1994).
Accordingly, it appears that specific molecules or compositions in regenerating fetal skin that are minimally present or not present at all in non-fetal skin (e.g., adult skin) are important in regenerating and promoting the appearance of skin.
Numerous compounds and techniques have been described in the art as being useful for promoting the condition of skin, especially of “aged” or wrinkled skin. Topical compounds include retinoic acid for stimulation of epidermal cell growth. Retinoids are well recognized as anti-wrinkle actives which help to reduce the subcutaneous effects of aging such as wrinkling, leatheriness, looseness, roughness, dryness, and mottling (hyper pigmentation) (see, U.S. Pat. Nos. 4,603,146 and 4,877,805). It has been postulated that retinoids act by producing inflammation, which causes thickening of the epidermis (acanthosis), and local intercellular edema, leading to exfoliation and improved skin texture and appearance. Use of L-ascorbic acid to stimulate fibroblast cell growth and collagen production has also been described (Hata R, Senoo H. J Cell Physiol 138:8-16. 1989). Techniques for promoting the condition of skin include deliberate methods of inducing skin irritation/injury through chemical (e.g., phenol peels), mechanical (e.g., dermabrasion), or thermal (e.g., lasers) means. Injury to the epidermis and/or dermis ultimately results in new cell growth and ECM deposition that may improve the overall appearance of skin.
Another skin conditions that often lead to skin damages is inflammation. In principle, the inflammatory and immune responses can be regulated through the use of drugs (In Goodman & Gilman's The Pharmacological Basis of Therapeutics eds. Hardman et al., Ninth Edition, McGraw-Hill publishing, 1996). Glucocorticoids and aspirin-like drugs (non-steroidal anti-inflammatory agents, NSAIDs) are the most widely used anti-inflammatory agents. NSAIDs are typically used to treat symptoms of inflammation (e.g. pain and fever). Corticosteroids are effective anti-inflammatory agents, having effects on virtually all inflammatory cells, but manifest significant adverse effects, such as inducing Cushingoid features, skin thinning, increased susceptibility to infection, effects on wound healing, and suppression of the hypothalamic-pituitary-adrenal axis. Other anti-inflammatory drugs presently available produce cytotoxic effects that reflect their initial employment as cancer chemotherapeutics, typically anti-neoplastic agents. Such drugs may kill cells indiscriminately, particularly those that proliferate rapidly. Methotrexate, however, is effective in treating rheumatoid arthritis at doses lower than those used to treat cancer (cytoreductive dose). Immunosuppressive agents, such as cyclosporin A and tacrolimus, are effective in preventing allograft rejection, but their use in treating autoimmune diseases has been limited by the development of severe side effects, particularly nephrotoxicity.
With specific regard to skin, topical or oral corticosteroids or antihistamines are the mainstays of therapy. However, corticosteroids have many undesirable side effects as listed above, while antihistamines may themselves elicit an allergic reaction when applied topically or cause excessive drowsiness when taken orally (Shai A, et al., Inflammation, dermatitis and cosmetics. Handbook of Cosmetic Skin Care. London: Martin Dunitz Ltd., pp. 135-146, 2001).
Hyperpigmentation is another common skin disease. Once present, hyperpigmentation is very difficult to treat. Because acquired hyperpigmentation can have a significant negative impact on cosmetic and psychosocial issues, much attention has focused on the treatment of hyperpigmentation. The current state of the art in hyperpigmentation offers many modalities, but none are completely satisfactory. The major limitation is that current modalities are primarily skin “bleaching” compounds that are fairly ineffective at treating established hyperpigmentation, especially dermal hyperpigmentation (Reviewed in Briganti S, et al., Pigment Cell Res. 16: 101-110, 2003). A variety of other substances have been proposed for the control or inhibition of skin pigmentation. Almost all of these substances work by either bleaching existing pigment or preventing new pigment synthesis by inhibiting the activity of tyrosinase, the principle rate-limiting enzyme in the production of melanin. For example, U.S. Pat. No. 6,123,959 describes the use of aqueous compositions comprising liposomes and at least one competitive inhibitor of an enzyme for the synthesis of melanin in combination with at least one non-competitive inhibitor of an enzyme for the synthesis of melanin. U.S. Pat. No. 6,132,740 describes the use of certain resorcinol derivatives as skin lightening agents. WO 99/64025A1 describes compositions for skin lightening which contain tyrosinase inhibiting extracts from dicotyledonous plant species indigenous to Canada. U.S. Pat. No. 5,580,549 describes an external preparation for skin lightening comprising 2-hydroxybenzoic acid derivatives and salts thereof as inhibitors of tyrosinase. WO 99/09011A1 describes an agent for inhibiting skin erythema and/or skin pigmentation, containing at least one carbostyril derivative and salts thereof. U.S. Pat. Nos. 5,214,028 and 5,389,611 describes lactoferrin hydrolyzates for use as a tyrosinase inhibitory agents. Additionally, a number of compounds and plant extracts are reported to have activity against hyperpigmentation, including ascorbic acid and derivatives thereof, kojic acid and compounds related thereto, licorice (glycyrrhiza) extract, and bearberry extract. While these chemical compounds and extracts are active in the reversal and prevention of hyperpigmentation, they can be irritating to the skin with prolonged use.
Despite the proposal of all these substances, the main products for treatment of hyperpigmentation contains hydroquinone, a well known active substance for skin de-pigmentation (e.g., see U.S. Pat. No. 6,139,854). However, hydroquinone can have serious side effects if applied over a long period of time. For example, the application of hydroquinone to skin may lead to permanent de-pigmentation, and thus to increased photosensitivity of the skin when exposed to ultraviolet light. Moreover, hydroquinone can be metabolized to benzoquinones, which are potent haematotoxic, genotoxic and carcinogenic compounds that can also induce the formation of radical species, predisposing cells to oxidative damage (Do Ceu Silva M, et al., Mutagenesis. 18:491-496, 2003). For that reason, in some countries hydroquinone is only allowed to be used for skin de-pigmentation in limited concentrations, and, in other countries, the product is banned completely for this application.
Therefore, there is a need for new and more effective methods for modulating skin conditions such as treating skin aging, inflammation and pigmentation which carry fewer significant and undesirable side effects.